Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition

Hartel, Ines; Ronellenfitsch, Michael; Wanka, Christina; Wolking, Stefan; Steinbach, Joachim P.; Rieger, Johannes

doi:10.3892/ijo.2016.3498

Cited by 8 publications

(6 citation statements)

References 24 publications

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“…A-769662 is a direct activator of AMPK (5). In glioblastoma (GB) cells, A-769662 has been shown to decrease glucose consumption and lactate production (6), and to protect GB cells from hypoxia-induced cell death, as well as from glucose deprivation (Lorenz et al, unpublished data). However, results obtained from neoplastic cells cannot easily be transferred into non-neoplastic astrocytic cells, as GB cells need to adapt to specific metabolic challenges in the tumor microenvironment and commonly rely on aerobic glycolysis for energy homeostasis (7).…”

Section: Introductionmentioning

confidence: 99%

AMPK activation protects astrocytes from hypoxia‑induced cell death

Strecker

Luger

et al. 2020

Int J Mol Med

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Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORc1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen. While neuroprotective approaches by definition focus on neurons, that are more sensitive under cell stress conditions, astrocytes play an important role in the cerebral energy homeostasis during ischemia. Therefore, the protection of astrocytic cells or other glial cells may contribute to the preservation of neuronal integrity and function. In the present study, it was thus hypothesized that a preventive induction of energy deprivation-activated signaling pathways via AMPK may protect astrocytes from hypoxia and glucose deprivation. Hypoxia-induced cell death was measured in a paradigm of hypoxia and partial glucose deprivation in vitro in the immortalized human astrocytic cell line SVG. Both the glycolysis inhibitor 2-deoxy-d-glucose (2dG) and the AMPK activator A-769662 induced the phosphorylation of AMPK, resulting in mTORc1 inhibition, as evidenced by a decrease in the phosphorylation of the target ribosomal protein S6 (RPS6). Treatment with both 2dG and A-769662 also decreased glucose consumption and lactate production. Furthermore, A-769662, but not 2dG induced an increase in oxygen consumption, possibly indicating a more efficient glucose utilization through oxidative phosphorylation. Hypoxia-induced cell death was profoundly reduced by treatment with 2dG or A-769662. On the whole, the findings of the present study demonstrate, that AMPK activation via 2dG or A-769662 protects astrocytes under hypoxic and glucose-depleted conditions.

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Section: Introductionmentioning

confidence: 99%

AMPK activation protects astrocytes from hypoxia‑induced cell death

Strecker

Luger

et al. 2020

Int J Mol Med

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“…Increasing evidence confirms that oncogenes play critical roles in the progression of human malignancies including glioma (23). Functionally, oncogenes were found to modulate the proliferation, apoptosis and metastasis of glioma cells (24).…”

Section: Discussionmentioning

confidence: 93%

B-cell CLL/lymphoma 3 promotes glioma cell proliferation and inhibits apoptosis through the oncogenic STAT3 pathway

Jiang

et al. 2016

International Journal of Oncology

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Aberrant expression of oncogenes and/or tumor suppressors play fundamental roles in the pathogenesis of glioma. B-cell CLL/lymphoma 3 (BCL3) was previously found to be a putative proto-oncogene in human cancers and the decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide in glioblastoma cells. However, its expression status, clinical significance and biological functions in glioma remain largely unknown. In the present study, the levels of BCL3 were overexpressed in glioma compared to normal brain tissues. Furthermore, high expression of BCL3 protein was confirmed by immunoblotting in glioma cells as compared with normal human astrocyte cell line. The positive expression of BCL3 was correlated with adverse prognostic features and reduced overall survival rate of glioma patients. BCL3 silencing resulted in prominent decreased proliferation, cell cycle arrest in G1 phase and increased apoptosis in U251 cells. In contrast, BCL3 overexpression in U87 cells remarkably facilitated proliferative ability and cell cycle progression and induced apoptosis. In vivo studies showed that BCL3 knockdown inhibited the tumor growth of U251 cells in a mouse xenograft model. Mechanistically, BCL3 positively regulated the abundance of STAT3, p-STAT3 and the downstream targets of STAT3 pathway including BCL2, MCL-1 and cyclin D1 in glioma cells. Furthermore, a positive correlation between BCL3 and STAT3 expression was observed in glioma specimens. Notably, we confirmed that STAT3 knockdown abolished the oncogenic roles of BCL3 in glioma. In conclusion, we suggest that BCL3 serves as an oncogene in glioma by modulating proliferation, cell cycle progression and apoptosis, and its oncogenic effects are mediated by the STAT3 signaling pathway.

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“…Furthermore, cetuximab has been shown to downregulate HIF-1α and thereby lactate dehydrogenase (LDH)-A, resulting in an inhibition of glucose consumption, lactate production, and intracellular ATP levels [ 26 ]. It is noteworthy that at least some EGFR inhibitors exert cytotoxicity preferentially under nutrient replete conditions [ 17 ]. Novel approaches even aim to improve tumor oxygenation concurrent to treatment [ 27 ] because hypoxia may promote tumor progression and resistance to current therapeutic strategies [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…These findings may constitute a rationale for a second-line treatment with bevacizumab. In glioma cells, pharmacological EGFR blockade confers protection from hypoxia-induced cell death [ 16 ], and starvation conditions attenuated the cytotoxic effect of EGFR inhibition [ 17 ]. Therefore, we hypothesized that chronic hypoxia induced by first-line bevacizumab therapy could antagonize the efficacy of second-line EGFR-antibodies in mCRC.…”

Section: Introductionmentioning

confidence: 99%

Cetuximab-Mediated Protection from Hypoxia- Induced Cell Death: Implications for Therapy Sequence in Colorectal Cancer

Urban

Maurer

Luger

et al. 2020

Cancers

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Monoclonal antibodies like cetuximab, targeting the epidermal growth factor receptor (EGFR), and bevacizumab, targeting the vascular endothelial growth factor (VEGF), are an integral part of treatment regimens for metastasized colorectal cancer. However, inhibition of the EGFR has been shown to protect human glioma cells from cell death under hypoxic conditions. In colon carcinoma cells, the consequences of EGFR blockade in hypoxia (e.g., induced by bevacizumab) have not been evaluated yet. LIM1215 and SW948 colon carcinoma and LNT-229 glioblastoma cells were treated with cetuximab, PD153035, and erlotinib and analyzed for cell density and viability. The sequential administration of either cetuximab followed by bevacizumab (CET->BEV) or bevacizumab followed by cetuximab (BEV->CET) was investigated in a LIM1215 (KRAS wildtype) and SW948 (KRAS mutant) xenograft mouse model. In vitro, cetuximab protected from hypoxia. In the LIM1215 model, a survival benefit with cetuximab and bevacizumab monotherapy was observed, but only the sequence CET->BEV showed an additional benefit. This effect was confirmed in the SW948 model. Our observations support the hypothesis that bevacizumab modulates the tumor microenvironment (e.g., by inducing hypoxia) where cetuximab could trigger protective effects when administered later on. The sequence CET->BEV therefore seems to be superior as possible mutual adverse effects are bypassed.

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Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition

Cited by 8 publications

References 24 publications

AMPK activation protects astrocytes from hypoxia‑induced cell death

AMPK activation protects astrocytes from hypoxia‑induced cell death

B-cell CLL/lymphoma 3 promotes glioma cell proliferation and inhibits apoptosis through the oncogenic STAT3 pathway

Cetuximab-Mediated Protection from Hypoxia- Induced Cell Death: Implications for Therapy Sequence in Colorectal Cancer

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